Psychological Medicine (2016), 46, 1427–1436. © Cambridge University Press 2016 doi:10.1017/S0033291715002998

OR I G I N A L A R T I C L E

Common and differential alterations of general emotion processing in obsessive-compulsive and social anxiety disorder S. Weidt1*, J. Lutz3, M. Rufer1, A. Delsignore1, N. J. Jakob4, U. Herwig3 and A. B. Bruehl2,3 1

Department of Psychiatry and Psychotherapy, University Hospital, University of Zurich, Zurich, Switzerland Behavioural and Clinical Neuroscience Institute and Department of Psychiatry, University of Cambridge, UK 3 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland 4 Sanatorium Kilchberg, Kilchberg, Switzerland 2

Background. Obsessive compulsive disorder (OCD) and social anxiety disorder (SAD) are characterized by biased perception and processing of potentially threatening stimuli. A hyper-reactivity of the fear-circuit [e.g. amygdala, anterior cingulate (ACC)] has been consistently reported using functional magnetic resonance imaging (fMRI) in SAD in comparison with healthy controls (HCs). Studies investigating the processing of specific emotional stimuli in OCD reported mainly orbitofrontal-striatal abnormalities. The goal of this study was to examine similar/common and differential neurobiological responses in OCD and SAD using unspecific emotional stimuli. Method. Fifty-four subjects participated: two groups (each n = 18) of outpatients with a current diagnosis of OCD or SAD, and 18 HCs. All subjects underwent fMRI while anticipating and perceiving unspecific visual stimuli with prior announced emotional valence (e.g. positive). Results. Compared to HCs, the combined patient group showed increased activation in amygdala, caudate and prefrontal/orbitofrontal cortex while anticipating unspecific emotional stimuli. Caudate was more active in the combined patient group during perception. A comparison between the OCD and the SAD samples revealed increased amygdala and decreased rostral ACC activation in OCD patients during perception, but no differences in the anticipation phase. Conclusions. Overall, we could identify common fronto-subcortical hyper-reactivity in OCD and SAD while anticipating and perceiving unspecific emotional stimuli. While differential neurobiological responses between OCD and SAD when processing specific stimuli are evident from the literature, differences were less pronounced using unspecific stimuli. This could indicate a disturbance of emotion regulation common to both OCD and SAD. Received 6 May 2015; Revised 30 November 2015; Accepted 16 December 2015; First published online 25 January 2016 Key words: Amygdala, anterior cingulate cortex, caudate, emotion processing, fMRI, obsessive compulsive disorder, perception, social anxiety disorder.

Introduction The ability of individuals to manage emotional experience and to adapt to a specific emotional context is disturbed in many psychiatric illnesses (APA, 2000; Bannon et al. 2002). In so-called emotion regulation disorders like major depression, anxiety, and obsessive compulsive disorder (OCD) such disturbances are a central characteristic of the disease (Bannon et al. 2002; Blair et al. 2010). These disturbances are reflected in neurobiological abnormalities (Fan & Xiao, 2013; Bruhl et al. 2014; Dutta et al. 2014).

* Address for correspondence: S. Weidt, MD, Department of Psychiatry and Psychotherapy, University Hospital, University of Zurich, Culmannstrasse 8, CH–8091 Zurich, Switzerland. (Email: steffi[email protected])

In OCD patients, obsessions are characterized by recurrent, persistent and irrational impulses, thoughts and images that cause significant negative emotions (APA, 2000). Compulsions are characterized by repetitive, ritualistic behaviours or mental acts that the patients feels obliged to perform to prevent harm, reduce negative emotions or neutralize obsessive thoughts (Bannon et al. 2002). Social anxiety disorder (SAD) patients are afraid of and avoid situations associated with potential exposure to unfamiliar social conditions (APA, 2000). In OCD patients there is growing evidence of orbitofrontal-striatal abnormalities compared to healthy control (HC) subjects (Kwon et al. 2009). Regional blood flow in the prefrontal cortex, insular (Schienle et al. 2005), and anterior cingulate cortex (ACC; Morgieve et al. 2014) has been found to be enhanced. Further evidence for orbitofrontal

1428 S. Weidt et al. abnormalities comes from diffusion tensor-imaging studies that generally report microstructural alterations of the orbitofrontal cortex (OFC), ACC and prefrontal cortex (Piras et al. 2013). Such fronto-striatal abnormalities are hypothesized to underlie executive deficits in OCD patients (de Wit et al. 2012; Gillan et al. 2015). Evidence for alterations in limbic circuits, particularly amygdala and insula, is scarce (Holzschneider & Mulert, 2011). In SAD, a recently published meta-analysis confirmed the hyper-reactivity of amygdala, insular cortex, ACC, and dorsolateral prefrontal cortex (DLPFC) compared to HCs; regardless whether specific or unspecific emotional stimuli were used during functional magnetic resonance imaging (fMRI; Bruhl et al. 2014). This confirms models of a hyper-reactive limbic system, which is not only hypersensitive to specific feared stimuli (i.e. negative faces) but to emotional stimuli in general (Shah et al. 2009; Bruhl et al. 2011). Taken together, fMRI studies suggest differential mechanisms in OCD and SAD but also overlapping abnormalities. However, studies directly comparing neurobiological similarities and differences between OCD and anxiety disorders have rarely been performed (Rauch et al. 1997). To investigate common and distinctive alterations in emotion processing in OCD and SAD we employed a paradigm involving the cued anticipation and perception of emotional stimuli (Bruhl et al. 2011). Notably, we used emotional pictures that were general and unspecific in content, chosen not to be provocative of social fears (e.g. angry/disapproving face) or of OCD (e.g. disorganized scene) and to be unambiguous in valence. Stimuli related to either one of the disorders would clearly have biased the circuits towards the respective disorder and would therefore have been difficult to compare across the disorders (Peterson et al. 2014). Many symptoms in OCD and anxiety disorders are not only evoked when actually facing a provoking stimulus, but also during the anticipation of these situations (Reuther et al. 2013; Rotge et al. 2015). Therefore, we used the cued anticipation and perception of general unspecific emotional stimuli as a model to investigate the network involved in general emotion processing across disorders. Our first aim was to compare a combined patient group (OCD and SAD) with HCs to find general abnormalities in brain function across both groups. The second aim was to compare OCD and SAD patients to identify neurobiological differences between these diseases. Our hypotheses were: (1) Emotion processing circuits (e.g. amygdala and insula) in the combined OCD-SAD patient group will be hyper-reactive compared to HCs. (2) Due to the scarcity of systematic

studies on emotional stimuli (unspecific or specific) comparing OCD and anxiety disorders, hypotheses of the direction of differential activation in certain regions of interest (ROIs) were difficult to reach. Taking studies comparing patients with HCs and mostly using specific stimuli as a basis, OCD patients would show hyper-reactivity in the striatum, caudate, ventromedial prefrontal cortex (VMPFC) and OFC compared to SAD patients, and SAD patients would show stronger activations in amygdala, and DLPFC compared to OCD patients. A further ROI was the rostral ACC.

Method and materials Subjects Fifty-four subjects participated in the study: 18 outpatients with a current diagnosis of OCD, 18 outpatients with a current diagnosis of generalized SAD, and 18 HCs. Participants in the three groups were matched for age and gender (Table 1). All participants gave their written consent prior to study procedures. All participants were right-handed (Annett, 1970). OCD and SAD were diagnosed by experienced clinicians and confirmed using the Mini International Neuropsychiatric Interview (M.I.N.I.; Sheehan et al. 1998). HCs were screened for the absence of any current or previous mental and neurological disorders in a semi-structured clinical interview based on the M.I.N.I. SAD and OCD patients did not differ in their selfratings for state and trait anxiety (State-Trait Anxiety Inventory; Spielberger et al. 1970) or depressive symptoms [Self-rating Depression Scale (SDS; Zung, 1965); and Beck Depression Inventory (BDI; Beck et al. 1961)] (Table 1). OCD patients showed higher depression levels than SAD patients in the clinical interview ratings [Hamilton Depression Scale (HAMD; Hamilton, 1960) and Montgomery–Asberg Depression Rating Scale (MADRS; Montgomery & Asberg, 1979)]. The severity of depression was on average mild and not clinically relevant. Patient groups did not differ in their medication level: nine patients of the OCD group were medicated with antidepressants (SSRI, n = 8; SNRI, n = 1) and six patients of the SAD group were medicated with antidepressants (SSRI, n = 5; SNRI, n = 1), (χ2 = 1.0, p = 0.371, df = 1). Most of the OCD patients reported obsessions and compulsion, two obsessions only and five compulsions only. We did not include patients with predominant hoarding symptoms. Exclusion criteria for all subjects were pregnancy, medication other than antidepressants, psychiatric diagnoses other than OCD/SAD and depression

Alterations of emotion processing in OCD and SAD

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Table 1. Demographic and psychometric description of the participants Measure mean ± S.D. (range)

HCs (N = 18)

SAD (N = 18)

OCD (N = 18)

Age, yearsa Gender Medication SDSa

31 ± 9.4 (20–57) 11 female 0/18 34.9 ± 3.8 (28.75–41.25)

31 ± 9.5 (20–53) 10 female 6/18 53.5 ± 12.2 (32.5–77.5)

31 ± 10.0 (20–56) 10 female 9/18 49.7 ± 13.5 (27.5–83.75)

STAI statea

35.0 ± 7.9 (23–50)

40.9 ± 10.5 (30–66)

42.2 ± 10.1 (30–66)

STAI traita

32.9 ± 5.4 (24–43)

52.2 ± 11.3 (33–74)

48.9 ± 13.7 (23–74)

BDI HAMD MADRS Rating of emotional stimulia

– – – nt: 5.16 (0.21) ps: 7.36 (0.65) ng: 2.99 (0.51)

7.9 ± 6.9 (1–23) 5.9 ± 5.3 (1–20) 6.1 ± 6.7 (1–26) nt: 5.08 (0.42) ps: 7.38 (0.91) ng: 2.59 (0.79)

11.0 ± 5.9 (2–23) 11.7 ± 8.0 (1–32) 13.4 ± 11.4 (1–45) nt: 4.97 (0.52) ps: 7.38 (0.95) ng: 2.24 (0.71)

Statistics F2,51 = 0.00, p = 1.0 χ22 = 0.15, p = 0.927 SAD/OCD: χ22 = 1.00, p = 0.371 F2,49 = 14.94, p < 0.001 HC/SAD: p < 0.001 HC/OCD: p < 0.001 SAD/OCD: N.S. F2,49 = 2.87, p = 0.066 HC/SAD: p = 0.07 HC/OCD: p = 0.03 SAD/OCD: N.S. F2,49 = 16.58, p < 0.0001 HC/SAD: p < 0.00001 HC/OCD: p < 0.00001 SAD/OCD: N.S. t25 = 1.24, N.S. t25 = 2.15, p = 0.043 t29 = 2.10, p = 0.046 nt: F2,50 = 0.93, N.S. ps: F2,50 = 0.001, N.S. ng: F2,50 = 5.21, p = 0.009 HC/SAD: N.S. HC/OCD: p = 0.002 OCD/SAD: N.S.

HCs, Healthy controls; SAD, social anxiety disorder; OCD, obsessive compulsive disorder; SDS, Self-rating Depression Scale; STAI, State-Trait Anxiety Inventory; BDI, Beck Depression Inventory; HAMD, Hamilton Depression Scale; MADRS, Montgomery–Asberg Depression Rating Scale; nt, neutral; ps, positive; ng, negative. a ANOVA with post-hoc comparisons.

(OCD/SAD had to be the prior diagnosis), neurological disorders, head trauma, excessive use or dependency of alcohol, cigarettes, caffeine and illegal drugs, and contraindications for fMRI.

Experimental design During fMRI, subjects performed an emotional anticipation and perception task that allows investigation of the anticipation and perception phase separately (for references see Bruhl et al. 2013). The task consists of 56 trials that each start with a cue (duration 1000 ms) depicting either a ‘positive’ symbol (∪), a ‘negative’ symbol (∩), or ‘neutral’ symbol (–) indicating the emotional valence of the upcoming picture, or a symbol (|) indicating ‘unknown’ (after which either a negative or positive picture appears, 50% chance). After the cue a blank black screen with a white fixation cross appeared for 6920 ms (cue + anticipation = 7920 ms = 4 MRI volumes/TR). Thereafter, the respective emotional picture from the International Affective Picture System

(IAPS; Lang et al. 2005) was presented for 7920 ms (4 × TR). A baseline period of 15 840 ms (8 × TR) allowed the mean blood oxygen level-dependent (BOLD) signal to wear off before the next trial. Each of the conditions (positive, negative, neutral, unknown) comprised 14 trials in a pseudo-randomized order. Subjects were instructed to consciously anticipate the cued emotional picture (anticipation) and then look at the presented emotional picture (perception). Because some of the negative pictures contained blood and other disgust-evoking aspects; after the scan, the participants were presented the stimuli again and were asked to rate them on valence for a 9-point Likert scale ranging from 1 (negative) to 9 (positive) and to report whether the pictures provoked typical disorder symptoms.

fMRI acquisition Imaging was performed with a 3.0 T GE Signa HD Scanner (GE Medical Systems, USA, 8-channel head

1430 S. Weidt et al. coil). Echo-planar imaging (EPI) was performed for fMRI [repetition time (TR)/echo time (TE) 1980/32 ms, 22 sequential axial slices, whole brain, slice thickness/ gap 5/0.5 mm, voxel size 3.4 × 3.4 × 5.0 mm, field of view 220 mm]. Altogether, 908 volumes were obtained within one run, 16 per trial. High-resolution 3D T1-weighted anatomical volumes were acquired (TR/ TE 9.9/2.9 ms; voxel size 1 × 1 × 1 mm, axial orientation) for co-registration with the functional data. Stimuli were presented via digital goggles (Resonance Technologies, USA). In addition, T2-weighted anatomical volumes were acquired to detect potential T2-sensitive brain abnormalities.

compared the mean beta-weights of each of the ROIs between OCD and SAD. To control for multiple comparisons, we applied the Benjamini–Hochberg procedure using a false discovery rate (FDR) of q = 0.1, which is similarly conservative as the Bonferroni comparison (McDonald, 2014). Differences in all group comparisons were conducted in SPSS v. 22 (SPSS Inc. USA), using Student’s t tests as well as two separate mixed ANOVAs for the anticipation and the perception period with the between-subjects factor ‘group’ (i.e. HCs v. SAD/OCD) and the within-subjects factors ‘condition’ (i.e. aps > ant/ang > ant/auk-ant and pps > pnt/ png > pnt, respectively).

fMRI analysis and statistics

Ethical standards

fMRI data were analysed using Brain Voyager QX 2.6 (Brain Innovation, The Netherlands; Goebel et al. 2006). Preprocessing of the functional scans included motion correction, slice scan-time correction, highfrequency temporal filtering, and linear detrending. The design matrix contained nine predictors [baseline; anticipation and perception of each positive (ps), negative (ng), neutral (nt), and unknown (uk) stimuli]. A hypothesis-driven ROI analysis within predefined spherical ROIs was performed. Anatomical ROIs were as follows: amygdala [according to the Talairach Client applet (Lancaster et al. 2000), diameter 10 mm, 515 mm3, centre x, y, z = 19/−9, −5, −17], caudate head/body (defined by averaging the clusters reported by van den Heuvel et al. 2011 and Gillan et al. 2015), transformation of MNI to Talairach coordinates using the Yale BioImage Suite (Lacadie et al. 2008), diameter 10 mm, 515 mm3, centre x, y, z = 10/−10, 14, 8), rostral ACC (according to Liu et al. 2011: diameter 10 mm, 515 mm3, centre x, y, z = 7/−7, 26, 24), DLPFC (according to Veltman et al. 2003: diameter 15 mm, 1791 mm3, centre x, y, z = 42/−42, 10, 34), anterior insula (according to Greenberg et al. 2015: diameter 15 mm, 1791 mm3, centre x, y, z = 34/−34, 13, 4), and VMPFC/OFC (according to Stern et al. 2011: diameter 20 mm, 4169 mm3, centre x, y, z = 0, 44, −2). On the subject-level, fixed-effects analyses were calculated for the anticipation phase including the contrasts ‘positive’ v. ‘neutral’ (aps > ant), ‘negative’ v. ‘neutral’ (ang > ant), and ‘unknown’ v. ‘neutral’ (auk > ant), and for the perception phase including the contrasts ‘positive’ v. ‘neutral’ (pps > pnt), and ‘negative’ v. ‘neutral’ (png > pnt). On the group level, we computed random-effects models for the comparison between OCD-SAD v. HCs and OCD v. SAD. In the first model we investigated general disorder effects extracting the mean beta-weights of each of the ROIs and compared these between the combined OCD-SAD patient group and HCs. In the second model we

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The study was approved by the ethics committee of the Canton of Zurich. Results Picture rating All participants rated the pictures in accordance with the valence (Table 1). We found no group difference in the rating of the neutral and positive stimuli between the groups. OCD patients rated the negative pictures significantly more negative than HCs, but not different from SAD patients. They reported that the pictures did not evoke OCD typical symptoms and there was no correlation between the subjective ratings and the activity in amygdala and insula (data not shown). Brain regions with differential activation in the combined OCD-SAD group compared to HCs In this group comparison (Table 2), the strongest differences were found in the left caudate head/body, where the anticipation of unknown, potentially negative stimuli as well as the perception of both negative stimuli resulted in a significantly stronger activation in the OCD-SAD patients than in HCs. During the unknown anticipation, OCD-SAD patients showed similarly increased activation compared to HCs in VMPFC and left amygdala. There were no ROIs in which HCs activated significantly stronger than OCD-SAD patients. The results of the mixed ANOVAs were identical and are given in the supplementary material (Supplementary Table S1, Supplementary Fig. S1). There was no significant main effect of depression (SDS) and no interaction between SDS and condition in the

Alterations of emotion processing in OCD and SAD

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Table 2. Common differences in OCD-SAD patients compared to healthy controls

Anatomical region Amygdala L Amygdala R Anterior insula L Anterior insula R DLPFC L DLPFC R Caudate Head/body L Caudate Head/body R VMPFC/OFC ACC L ACC R

Talairach BA (x/y/z) −19/−5/−17 19/−5/−17 −34/13/4 34/13/4 −42/10/34 42/10/34 −10/14/8

Vol (mm3)

Aps-ant t/p

Ang-ant t/p

Auk-ant t/p

Pps-pnt t/p

Png-pnt t/p

515 515 1791 1791 1791 1791 515

1.921/0.060 1.223/0.227 1.268/0.211 0.454/0.652 0.062/0.951 −0.143/0.887 1.745/0.087

1.352/0.182 0.786/0.436 −0.302/0.764 −1.069/0.290 0.673/0.504 0.266/0.791 −0.286/0.776

2.377/.021 1.552/.127 0.908/.332 0.021/.984 0.260/0.796 −0.567/0.573 3.110/.003

10/14/8

515

1.880/0.240

−0.364/0.717

1.692/.097

1.950/0.057

2.371/0.021

0/44/−2 −7/26/24 7/26/24

4169 515 515

1.883/0.065 0.302/0.764 −0.124/0.902

−0.029/0.977 −1.155/.253 −0.982/.330

3.821/.0004 0.917/.363 0.883/0.382

1.936/0.058 2.183/0.034 1.670/0.101

0.711/0.481 0.633/0.529 1.222/.227

0.049/0.961 0.514/0.610 0.063/0.950 0.086/0.932 0.724/0.472 −0.195/0.847 1.119/0.268 −0.380/0.706 −0.440/0.662 −0.722/.473 −0.197/0.844 0.575/0.567 2.427/0.019 2.731/.009

OCD, Obsessive compulsive disorder; SAD, social anxiety disorder; aps, anticipation of positive stimuli; ant, anticipation of neutral stimuli; ang, anticipation of negative stimuli; auk, anticipation of unknown stimuli; pps, perception of positive stimuli; pnt, perception of neutral stimuli; png, perception of negative stimuli, L, left, R, right; DLPFC, dorsolateral prefrontal cortex; VMPFC/OFC, ventromedial prefrontal cortex/orbitofrontal cortex; ACC, rostral anterior cingulate cortex. Contrasts marked in bold/underlining are statistically significant. Statistical threshold: q < 0.1 (FDR corrected), contrasts given in italics are significant at corrected trend level (q < 0.25 FDR).

ANOVA. There was no correlation between the betaweights in the ROIs and the scores of depression (SDS) and trait anxiety (STAI-T) across the groups. Comparison between the patient groups Overall, we found fewer differences between the two patient groups than between the combined OCDSAD patient group and HCs. We found no significant differences between SAD and OCD during the anticipation. During the perception of emotional stimuli, the right amygdala was more active in OCD for negative stimuli, with a trend during the positive perception condition. At a trend level the right rostral ACC was less active during the perception of negative stimuli in OCD patients (Table 3).

patient group. During the perception period we found a higher activation of the caudate in the combined OCD-SAD patient group. The comparison between the patient groups revealed no differences during the anticipation of emotional stimuli. During the perception, the amygdala was more and the rostral ACC less activated in OCD than in SAD patients. Our results are consistent with our hypotheses that emotion processing circuits are more strongly activated in OCD-SAD patients than in HCs when perceiving unspecific emotional stimuli. However, differences between OCD and SAD were rather small and did not demonstrate the hypothesized hyper-reactivity of the limbic circuit in SAD or of fronto-striatal areas in OCD.

Discussion

Common alterations in OCD and SAD patients compared to HCs

To our knowledge, this is the first study to compare the neural correlates of general emotion processing in OCD and SAD with disease-unspecific emotional stimuli. Our aim was to reveal common and differential neurobiological alterations in emotional processing in patients with OCD and SAD during anticipation and perception of these emotional stimuli. The main findings when comparing the combined OCD-SAD patient group to HCs were the hyperreactivity in left amygdala, caudate, and VMPFC/ OFC during the anticipation period in the OCD-SAD

As hypothesized, activation in the amygdala and VMPFC/OFC was higher in OCD-SAD patients than in HCs during the anticipation of ‘unknown’ stimuli. The amygdala has been consistently found to be hyper-reactive in patients with SAD and OCD compared to HCs in response to emotional stimuli (Cardoner et al. 2011; Bruhl et al. 2014; Simon et al. 2014), potentially reflecting a common alteration in both diseases and also in other emotion regulation disorders, like major depression (e.g. Grotegerd et al. 2014).

1432 S. Weidt et al. Table 3. Differences between the two disorders (OCD > SAD)

Anatomical region Amygdala L Amygdala R Anterior insula L Anterior insula R DLPFC L DLPFC R Caudate Head/ body L Caudate Head/ body R VMPFC/OFC ACC L ACC R

Talairach (x/y/z)

Vol (mm3)

Aps-ant t/p

Ang-ant t/p

515 515 1791 1791 1791 1791 515

0.370/0.714 −0.016/0.987 0.877/0.387 1.289/.206 −0.619/.540 −0.367/0.716 0.375/0.710

−0.333/0.741 0.260/0.797 0.672/0.506 0.539//0.593 −0.667/0.509 −0.866/0.392 1.558/0.128

10/14/8

515

0.401/0.691

1.308/.199

0/44/−2 −7/26/24 7/26/24

4169 515 515

0.566/0.575 0.563/0.577 1.233/.226

−0.225/0.824 0.682/.500 1.098/0.280

−19/−5/−17 19/−5/−17 −34/13/4 34/13/4 −42/10/34 42/10/34 −10/14/8

Auk-ant t/p

Pps-pnt t/p

Png-pnt t/p

0.529/0.600 0.352/0.727 1.120/0.270 1.955/.059 −0.766/0.449 −0.576/0.568 0.804/0.427

1.367/.181 2.139/.040 0.707/.484 −0.436/0.666 1.000/.324 0.746/0.461 0.951/0.348

1.722/.094 2.319/.027 0.158/0.876 0.074/0.941 0.473/0.639 0.516/0.609 1.075/.290

0.950/0.349

−0.152/0.880

0.236/0.815

−0.264/0.793 1.509/0.141 1.590/.121

0.807/0.425 −0.152/0.880 −0.346/.731

−0.311/0.757 −1.618/.115 −2.353/.025

OCD, Obsessive compulsive disorder; SAD, social anxiety disorder; aps, anticipation of positive stimuli; ant, anticipation of neutral stimuli; ang, anticipation of negative stimuli; auk, anticipation of unknown stimuli; pps, perception of positive stimuli; pnt, perception of neutral stimuli; png, perception of negative stimuli, L, left, R, right; DLPFC, dorsolateral prefrontal cortex; VMPFC/OFC, ventromedial prefrontal cortex/orbitofrontal cortex; ACC, rostral anterior cingulate cortex. Contrasts marked in italics/underlining are statistically significant at corrected trend level (q < 0.25 FDR).

The VMPFC/OFC is supposedly involved in emotion processing, particularly in attributing salience during the anticipation of stimuli (Diekhof et al. 2012). Previous studies have reported stronger activation in SAD and OCD (Adler et al. 2000; Quadflieg et al. 2008; Blair et al. 2010), meta-analyses in SAD (Bruhl et al. 2014) and OCD (Rotge et al. 2008) and support the increased sensitivity of emotion processing circuits as a common feature. In our study, during the anticipation of ‘unknown’ emotional stimuli the caudate was significantly more activated in the combined patient group compared to HCs, but not different between the OCD and SAD patients. For HCs, there is evidence of an involvement of the caudate in emotional processing (Alexander et al. 1990; Arsalidou et al. 2013). In SAD, a recently published meta-analysis reported mixed results in the caudate compared to HCs (Bruhl et al. 2014). In OCD the majority of studies found increased reactivity in the caudate (Rauch et al. 1994; Saxena et al. 2004). Taken together, our results and results of previous studies suggest that the caudate plays a role in emotional processing and is part of the emotion processing circuit. Unexpectedly, insula activation did not differ between HCs and OCD-SAD patients. Insula activation has not only been found to be increased in patients suffering from SAD and OCD (Schienle et al. 2005; Bruhl et al. 2014), but also in anxious HCs during the anticipation of ‘aversive’, ‘positive’ and ‘uncertain’ stimuli (Simmons et al. 2011). Previous studies using

disease-unspecific stimuli reported mixed results of insula hypo-activation (Sareen et al. 2007) or less pronounced hyper-activation (Schienle et al. 2005; Shah et al. 2009). However, it is noteworthy that some studies showed a correlation of insula activity with trait anxiety in healthy populations (Stein et al. 2007; Simmons et al. 2011). Therefore, we would have expected increased insular activation in the OCDSAD patient group already due to their significantly higher trait anxiety scores. Differential activation between OCD and SAD Overall we found no differential activations between the two patient groups during the anticipation period. During the perception period the amygdala was slightly more active in OCD than in SAD patients. This result was rather surprising, especially as a large metaanalysis in SAD patients found markedly increased activation of the amygdala region compared to HCs (Bruhl et al. 2014), but OCD studies have reported mixed results or even hypo-activation of the amygdala region compared to HCs (Cannistraro et al. 2004; Cardoner et al. 2011). Potential reasons for this finding could be: (1) The use of unspecific stimuli. It is possible that disease-specific emotional stimuli might have revealed differential activation patterns. (2) Our findings might point to disease-overarching mechanisms of amygdala activation in these two disorders when stimulated with unspecific emotional pictures, reflecting an unspecific emotional vulnerability

Alterations of emotion processing in OCD and SAD (Simon et al. 2010). Finally, (3) amygdala reactivity might be specifically modulated by certain dimensions of OCD symptoms (Via et al. 2014). We did not differentiate between different OCD symptoms but included OCD patients regardless of their symptoms. Our results are therefore likely to be representative for a typical clinical population of OCD patients. However, as there is at least some evidence that certain functional alterations might be associated with certain OCD symptoms (Via et al. 2014) our results might be influenced by the rather mixed OCD sample. While we found the VMPFC/OFC to be hyperreactive compared to HCs, we found no differences between OCD and SAD patients. Until now, only few studies have used unspecific emotional stimulation. In SAD (Shah et al. 2009; Bruhl et al. 2011; Gaebler et al. 2014) and in OCD (Phillips et al. 2000) these studies mainly reported no clear difference in the OFC compared to HCs, and only one study in OCD reported hyper-reactivity (Schienle et al. 2005). This very limited evidence highlights the need for future studies on alterations in general emotion processing beyond disease-specific stimuli. When comparing OCD and SAD, the rostral ACC was more activated in SAD during the perception of negative pictures which, however, was not a strong effect. In OCD, structural data consistently reported significantly smaller ACC volumes than in HCs (Rotge et al. 2009; Radua et al. 2010; de Wit et al. 2014), pointing towards a disease-related alteration in this area. fMRI and PET studies provided evidence for a hyper-activation in ACC areas in OCD (Rauch et al. 1994; Morgieve et al. 2014). In SAD, the ACC has similarly been shown to be hyper-reactive, while structural abnormalities have rarely been found (Bruhl et al. 2014). Therefore, stronger activation in SAD during the perception of negative stimuli compared to OCD is possibly linked to known structural brain differences in OCD particularly in the ACC [de Wit et al. 2014; meta-analysis (Eng et al. 2015)], which might reduce the measurable activation and could therefore reflect differential pathophysiological processes between OCD and SAD. When comparing studies investigating structural brain differences (grey matter, white matter) between HCs and patients with OCD and with SAD, the results in OCD seem mainly consistent [recent meta-analyses on grey-matter changes (Piras et al. 2015), white-matter changes (Piras et al. 2013; Radua et al. 2014), and their combination (Eng et al. 2015)], particularly in ACC, VMPFC/ OFC and basal ganglia. However, in SAD, studies have reported rather mixed results, at least at the greymatter level (for review see Bruhl et al. 2014). This could indicate that neurobiological factors might play a more important role in OCD compared to SAD.

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While the caudate was hyper-active in OCD-SAD patients compared to HCs, there was no differential activation between OCD and SAD patients. The caudate hyper-activation might therefore reflect an unspecific increased arousal response (Kumar et al. 2014) to disease-unspecific emotional stimuli. Overall, the use of disease-unspecific stimuli might have evoked nonmaximal reactions and activations such that compensatory mechanisms might have reduced the differences between the groups. Some limitations that might be important for the interpretation of the present results should be noted. First, in contrast to HCs, subjects in both patient groups received medication, potentially explaining differences between HCs and the combined patient group. Therefore, we think that the current patient samples are representative for typical clinical populations. Second, OCD patients rated the negative pictures more negative than HCs. Some of the negative pictures contained blood and other disgust-evoking aspects, which might explain the negative rating. However, we found no correlation between the subjective ratings and the activity in amygdala and insula and patients reported that the pictures did not evoke disease-typical symptoms. Conclusion To conclude, we found that patients with OCD and SAD show very similar alteration patterns in fronto-striatal and limbic regions during unspecific emotional stimulation. Compared to HCs these regions were hyper-activated in the combined OCD-SAD sample. These findings potentially point to diseaseoverarching mechanisms of neural activation during emotional processing. Supplementary material For supplementary material accompanying this paper visit http://dx.doi.org/10.1017/S0033291715002998. Acknowledgements We acknowledge funding support from the Swiss National Science Foundation. No granting or other outside parties had any role in the study’s design or orchestration, including data collection and analysis, our decision to publish, or preparation of the manuscript. S.W. has received grants from the Gottfried and Julia Bangerter-Rhyner Foundation, Novartis Foundation for medical-biological research, University of Zurich – career development grant ‘Filling the gap’. J.L. is supported by the Swiss National Science Foundation. M.R. has received Speaker honoraria from AstraZeneca and

1434 S. Weidt et al. Lundbeck Institute, research grants from the Gottfried and Julia Bangerter-Rhyner Foundation and the Novartis Foundation for medical-biological research. A.D. has received grants from the University of Zurich ‘Matching Fund’ and from the ‘Johnson Foundation’. U.H. has received a grant from the Swiss National Science Foundation. A.B.B. is in receipt of a Fellowship from the Swiss Foundation for Grants in Biology and Medicine (SFGBM) and the Swiss National Science Foundation.

Declaration of Interest None.

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